Transcript Transmission electron micrograph of poliovirus type I

Picornaviruses
Genera of the family Picornaviridae
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Enterovirus
Parechovirus
Rhinovirus
Hepatovirus
Aphtovirus
Cardiovirus
Structure of virion
• Ss +RNA.
• Virion is icosahedral 22-30nm
in diameter.
• Capsid has 60 copies of 4
proteins:
– VP1, VP2, and VP3 are exposed
on the virion surface,
– VP4 lies buried in close
association with the RNA core.
• Immunogenic sites are located
on the external parts of the
capsid.
Reproduction Cycle of Picornaviruses
Unique properties of human Picornaviruses
• Small nonenveloped viruses.
• Because they contain no essential lipids, they are
ether, acidic pH, and detergents resistant.
• Rhinoviruses are labile at acidic pH.
• They replicate in the cytoplasm.
• Most viruses are cytolytic.
• Picornaviruses do not have a common groupspecific antigen. Each serotype has a type-specific
antigen, which is identifiable by neutralization tests
GENUS ENTEROVIRUSES
The enterovirus genus is so-called because these viruses
generally replicate in the intestine.
History
• Poliovirus - first identified by Karl Landsteiner in
1908 by inoculation of specimens into monkeys. The
virus was first grown in cell culture in 1949 which
became the basis for vaccines.
• Coxsackieviruses - were identified in 1948 by
inoculation into newborn mice from two children with
paralytic disease. These agents were named
coxsackieviruses after the town in New York State.
• Echoviruses - were identified in 1951 which
produced cytopathic changes in cell culture and was
nonpathogenic for newborn mice.
• More recently, new enterovirus types have been
allocated sequential numbers (68 - 71).
Pathogenesis of enteroviruses infections
• Routes of transmission:
– fecal-oral,
– via salivary and respiratory droplets,
– via conjunctival secretions and skin lesion exudates,
• Portal of entry: nasopharynx and intestinal
mucosa.
• Replication: in the nasopharyngeal and intestinal
epithelium and regional lymph nodes.
• Spread: by the bloodstream in the
reticuloendothelial system and to target organs
such as the spinal cord, brain meninges, heart, liver
and skin.
• From the CNS the virus travel via neural pathways
to skeletal and heart muscles.
Pathogenesis of enterovirus infections
Pathogenesis of enteroviruses infections
Cox = Coxsackie virus A or B, Hep A = hepatitis A virus,
Echo = echovirus, Polio = poliovirus
Poliovirus
3 serotypes of poliovirus (1, 2, and 3) but
not common antigen.
Humans are the only susceptible host
Transmission electron
micrograph of
poliovirus
Polio endemic countries (where polio is prevalent)
EPIDEMIOLOGY
• Source — human with clinical and subclinical
infection.
• Transmission: primarily via the fecal-oral, by
ingesting contaminated food or water .
• Incubation period - 3 to 35 days, on average —
7-14 days.
• Polio is most infectious between 7 and 10 days
before and after the appearance of symptoms, but
transmission is possible as long as the virus remains
in the saliva (2 weeks) or feces (3-5 months).
Pathogenesis of polio viruses infection
• The alimentary phase: Primary replication in
the oropharyngeal and intestinal mucosa.
• The lymphatic phase: Virus spreads to the
tonsils and Peyer's patches.
• The viremic phase: The virus is carried by the
bloodstream to various internal organs and
regional lymph nodes.
• The neurologic phase: The virus spreads
hematogenously to the spinal cord or brain
stem or to both. Damage results in paralysis of
the muscles innervated by the affected motor
nerves. Paralysis is usually irreversible, and
residual paralysis remains for life.
Pathogenesis of polio viruses infection
Poliovirus can survive
and multiply within the
blood and
lymphatics for 17
weeks
• Poliomyelitis - infammation of the gray
(polios) anterior matter of the spinal cord
(myelos)
• Death of motor neurons
• Sensory neurons unaffected
The location of motor neurons in the
anterior horn cells of the spinal column
• Diagram of healthy
spinal cord section
with nerve cells
(motor nerve cells)
branching to
muscles
• Neuron structure
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Degeneration of Nerve cells (Neurons)
during Acute Polio
• The nerve cell is invaded
by poliovirus
• One of the nerve cells has
been infected by the
poliovirus, while its
neighbor has not
• Destruction of the
infected nerve cells
results a lack of nerve
supply to the muscles
• If this process occurs on
a large enough scale, it
can result in loss of
muscular function, and
can cause weakness or
paralysis
Recovery From Acute Paralytic Polio
• Immediately following
paralytic polio, surviving
motor nerve cells in the brain
stem and spinal cord extend
new branches to re-connect
the nerve cell to the muscle.
These are called sprouts.
• The new sprouts are now
capable of triggering
contraction in the muscles
and muscle function can be
partially or fully regained
• Thus, many motor nerve cells end up
supplying several times the number of muscle
fibers they would normally supply.
• Recovery is usually complete in 6 to 8 months.
A single motor
neuron that once
controlled 200
muscle cells might
control 800 to 1000
cells.
Mechanism of Post-Polio Syndrome
• These new sprouts are not
indefinitely stable.
• After many years these
motor neurons begin to
break down, causing new
muscle weakness.
Clinical syndromes associated with polio viruses
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Inapparent (subclinical) infection.
Abortive infections (a minor influenza-like illness).
Aseptic meningitis.
Encephalitis.
Paralytic poliomyelitis:
– spinal poliomyelitis - complete flaccid paralysis of one or more limbs;
– bulbar poliomyelitis - paralysis of neck and respiratory muscles;
– bulbospinal poliomyelitis.
• Post-polio syndrome: the virus is no longer present. It may
occur many years after the infection and involves further loss
of function in affected muscles as a result of further neuron
loss.
Outcomes of poliovirus infection
Outcome
Asymptomatic
Proportion of cases
90–95%
Minor illness
4–8%
Aseptic meningitis
1–2%
Paralytic poliomyelitis
0.1–0.5%
Spinal polio
79% of paralytic cases
Bulbospinal polio
19% of paralytic cases
Bulbar polio
2% of paralytic cases
Symptoms of poliomyelitis
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high fever, headache,
stiffness in the back and neck,
asymmetrical weakness of muscles, sensitivity to touch,
difficulty swallowing,
muscle pain,
paresthesia (pins and needles),
constipation, or difficulty urinating.
• Paralysis generally develops 1 to 10 days after early
symptoms begin, progresses for 2 to 3 days, and is
usually complete by the time the fever breaks.
Egyptian stele from the 18th dynasty showing a victim
of polio with a withered leg
Children with polio sequelae
Muscle paralysis can sometimes
result in skeletal deformities,
tightening of the joints and
movement disability.
IMMUNITY
• Active immunity:
• Life-long, type-specific
• Mechanism:
– Local: IgA are present in the tonsils and
gastrointestinal tract, and are able to block virus
replication;
– Humoral: IgG and IgM can prevent the spread of the
virus to motor neurons of the CNS.
• Passive immunity: Maternal antibodies cross
the placenta, and protect the infant from polio
infection during the first 2-3 months of life.
• Jonas Edward Salk (1914-1995) was
an American medical researcher
and virologist, developed the
first inactivated polio vaccine in 1952.
• Albert Sabin (1906-1993), an American
medical researcher, developed an oral
attenuated live polio vaccine in 1955 and
perfected and tested widely in 1961
Prevention
• Intramuscular Poliovirus Vaccine (IPV)
– consists of formalin inactivated virus of all 3 serotypes.
– Produces serum antibodies only: does not induce local
immunity and thus will not prevent local infection of the gut.
– However, it prevent paralytic poliomyelitis since viraemia is
essential for the pathogenesis of the disease.
– No risk of vaccine-related disease.
• Oral Poliovirus Vaccine (OPV)
– Consists of live attenuated virus of all 3 serotypes.
– Produces local immunity through the induction of an IgA
response as well as systemic immunity.
– Lifelong immunity.
– Rarely causes paralytic poliomyelitis, around 1 in 2 million
doses.
Serum and secretory antibody response to intramuscular
inoculation of IPV and to live attenuated OPV
Inactivated polio vaccine
Live polio vaccine
Schedule of immunization
• New guidelines suggest
administration of the IPV for the
first two doses to eliminate the risk
of vaccine-related paralytic polio
disease followed by two doses of
the OPV on a schedule of
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2 months of age (inactivated),
4 months (inactivated),
12-18 months (oral),
4-6 years (oral).
• In children with varies immune
deficiencies the live vaccine is
not used!
Clinical syndromes associated with
non-polio Enteroviruses
• Aseptic meningitis, encephalitis and ascending
paralysis.
• Common cold syndrome.
• Coxsackie A
– Herpangina (sore throat, fever, vesicles).
– Hand-foot-and mouth disease.
• Coxsackie B
– Myocarditis, pericarditis.
– Pleurodynia (Bornholm’s disease or Devil’s Grippe).
• ECHO viruses: exanthematous disease (rash).
• Enterovirus 70: acute hemorrhagic conjunctivitis.
• Enterovirus 71: severe CNS disease.
Diseases associated with Enteroviruses
Syndrome
Asymptomatic infection
Paralytic disease
Meningitis-encephalitis
Respiratory infection
Hand-foot-mouth disease
Herpangina
Pleurodynia
Carditis
Rash disease
Hemorr. conjunctivitis
Polio
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Cox A Cox B Echo
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Aseptic meningitis and encephalitis
• Both Coxsackie virus A and B can cause aseptic meningitis
which is so-called because it is not of bacterial origin.
• Headache, stiff neck, fever, avoidance of light, and eye pain
are characteristic. Drowsiness may be prominent, and other
symptoms include sore throat, cough, muscle pain, and rash.
• Occasionally, not only the meninges, the covering around the
brain and spinal cord is infected, but also brain tissue itself,
producing encephalitis.
• The illness resolves after about a week or so, and permanent
damage is unusual.
• Enteroviruses can also produce the Guillian-Barré syndrome,
which involves weakness and paralysis of the extremities
and even the muscles of respiration.
• The disease is most prevalent in the summer and fall.
Hand-foot-and-mouth disease
 This is an exanthem (a rash) caused by Coxsackie type A16.
Symptoms include fever and blisters on the hands, palate and
feet, which lead to ulcers. Symptoms generally resolve within a
week.
Herpangina
•Coxsackie viruses A can cause a
fever with painful ulcers on the
palate and tongue leading to
problems swallowing and vomiting.
Symptoms can persist for several
weeks.
Hemorrhagic
conjunctivitis
EV70 have been linked as the
causative agents of acute
hemorrhagic conjunctivitis
 Pleurodynia, epidemic myalgia, devil's grip
and Bornholm disease
 - Onset is usually abrupt, with fever, headache,
and stabbing pain in muscles of the chest
and/or upper abdomen. Pain occurs as acute
episodes, lasting 30 minutes or so and is
intensified by respiration and movement and
may persist for a few weeks.
 - The disease is self-limiting, but relapses, with
recurrences of fever and other symptoms, are
common.
 - Occasional complications include pleuritis
and orchitis.
 Myocarditis and/or pericarditis involves infection of
the heart muscle (myocardium) and the covering
around the heart (pericardium). The disease usually
begins as an upper respiratory tract infection with
cough, shortness of breath, and fever. Chest pain,
increasing shortness of breath, irregularities of cardiac
rhythm, and heart failure sometimes develop.
 Neonatal
myocarditis
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accompanied
by
involvement of various organs, especially the CNS
and liver.
 Onset may be abrupt, with lethargy, feeding
difficulties, fever and often signs of cardiac or
respiratory distress. The infant may die within days or
may recover over the next few weeks.
 These infections are acquired from infected
mothers or during a nursery outbreak.
The echoviruses
• (enteric, cytopathic, human, and orphan
viruses) are grouped together because they
produce cytopathogenic effects in cell cultures
but generally are not pathogenic for mice, and
they differ antigenically from the polioviruses.
• They were first named "orphan viruses"
because their relationship with disease was
obscure.
Maculopapular Rash.
Echovirus 19
Echoviruses cause diseases:
aseptic meningitis,
encephalitis,
paralysis,
febrile rash,
minor respiratory illness,
diarrhea.
Laboratory diagnosis of enteroviruses infection
• 1. Culture and isolation of viruses from feces, pharyngeal swabs,
saliva, nasal aspirates, skin lesions, conjunctiva, cerebrospinal fluid,
spinal cord, brain, heart, and blood.
Choice of Virus Isolation System
Tissue culture
Suckling mice
Polioviruses
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Coxsackieviruses group A
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Coxsackieviruses group B
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Echoviruses
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Virus
Identification: NtT, CFT, ELISA, HAIT.
Normal cell culture
CPE of enteroviruses in
monkey kidney cells
• Coxsackieviruses are differentiated by their
pathogenicity for suckling mice and by
classification of their antigenicity.
– Group A viruses produce a diffuse myositis
with acute inflammation and necrosis of fibers
of voluntary muscles.
– Group B viruses produce focal degeneration
in the brain and spinal cord, spastic paralysis,
and necrosis of fat pads between the
shoulders.
Laboratory diagnosis of enteroviruses infection (2)
• 2. Serology (four-fold or greater rise in
neutralizing antibody titer between paired sera
or high IgM titers to a single serotype):
– NT;
– CFT;
– IF;
– ELISA;
– HAIT.
Enterovirus 71 infection
• Transmission:
– fecal-oral,
– by respiratory droplets,
– through contact with the fluid in the blisters.
• The virus can be in the faeces for at least 2 months after
symptoms develop. A person is infectious for as long as the virus
is present in the faeces.
• Incubation period: 3-5 days.
• Infection may be asymptomatic, mild or severe neurological
disease. After fever develops it usually takes 1-3 days before
meningitis occurs, but paralysis can occur within 10-30 hours after
symptoms begin.
• Treatment usually focuses on the person's symptoms.
• Prevention:
• Good hygiene is the single most effective way of preventing the
spread of the disease. Hands should be washed thoroughly in
soap and water for at least 15 seconds and then dried thoroughly.
Entervirus 71
Symptoms:
• rashes,
• diarrhea,
• colds,
• hand-foot-mouth disease,
• myocarditis,
• paralytic poliomyelitis-like disease,
• bulbar and brain encephalitis, meningitis,
• rapidly fatal pulmonary edema and
hemmorrhage.
Hand-foot-mouth disease caused by the
Enterovirus 71
• It is spread from person to person by direct contact with the
nasal discharge, saliva, and fluid from the rash of an infected
person.
• There is no specific treatment for the infection. Symptomatic
treatment is given to provide relief from fever, aches and pain.
The throat and tonsils develop
small ulcers while the hands,
feet, and diaper area are
affected by a rash with
characteristic vesicles (very
small blisters). This is usually
a mild illness with the rash
healing in 5 to 7 days.
Pathogenesis
of severe
EV71
infections
Parechoviruses
• Six types have been identified:
– human parechovirus 1 (formerly ECHO-virus 22),
– human parechovirus 2 (formerly ECHO-virus 23),
– human parechoviruses 3, 4, 5 and 6.
• More than 95% of humans are infected by
human parechoviruses early in life, within 2 to 5
years of age.
• Cause:
– mild, gastrointestinal or respiratory illness,
– myocarditis and encephalitis.
Rhinoviruses
117 serotypes are responsible for
almost 35 % of colds
• In this scanning electron
micrograph rhinoviruses are
seen infecting the surface of a
nasal epithelial cell
(nasopharynx region).
Rhinovirus is made up of
a cubical protein capsid
with a genome of one
strand of RNA
Rhinoviruses infection
• Transmission:
– mainly by respiratory droplets;
– hand to hand transmission (via nasal and ocular secretions).
• Incubation period – 1-5 days, sometimes – few hours.
• Symptoms:
– Sneezing, nasal clogging, runny nose, sore throat
– ~7 days acute illness, 2-3 weeks cough.
• Complications:
– Chronic bronchitis.
– Sinusitis.
– Otitis media.
• Immunity: 1-2 years,
type-specific.
• Therapy: interferon.
Laboratory diagnosis
• Virus Isolation from nasopharyngeal
secretions in cell culture
–Identification: NT, IF.
• Serology: NT.